A. Developmental Renal Physiology

Glomerular Filtration Rate (GFR) Development: - At birth, neonatal GFR is approximately 20-40 mL/min/1.73 m² (vs. adult 100-130 mL/min/1.73 m²) - GFR doubles by 2 weeks of age and approaches adult levels by 2-3 months - The relationship is NOT linear—GFR is lowest in the first 24-48 hours of life - Premature infants have even lower initial GFR and slower maturation trajectory

Creatinine Interpretation: - Serum creatinine at birth reflects maternal filtration (maternal creatinine crosses placenta) - Neonatal creatinine declines over first 5-7 days of life as maternal contribution clears - Interpreting neonatal creatinine >1.2 mg/dL at 24 hours requires caution—recheck at 48-72 hours - By 7 days of age, neonatal creatinine should be 0.4-0.8 mg/dL; if persistently elevated, consider renal pathology

Key Formula: - Schwartz equation for children >2 years: eGFR = (0.413 × height in cm) / creatinine (mg/dL) - For infants <2 years, eGFR calculation is unreliable; use cystatin C if available - Cystatin C is less dependent on age, muscle mass, and diet than creatinine

B. Electrolyte and Acid-Base Immaturity

• Neonatal kidneys cannot concentrate urine maximally until 6-12 months of age (max osmolality ~600 mOsm/kg vs. adults 1200)
• Bicarbonate reabsorption threshold is lower in neonates (15-18 mEq/L vs. adult 22-24)
• Inability to acidify urine maximally; therefore, neonates cannot handle high acid loads efficiently
• Clinical implication: Neonates are susceptible to both hypernatremic and hyponatremic dehydration

A. Vesicoureteral Reflux (VUR)

Epidemiology: - Incidence: 1-2% of children; present in 30-50% of children with UTI - Genetic predisposition: familial in 30-50% of cases - Higher prevalence in male neonates diagnosed prenatally

Pathophysiology: - Incompetence of the ureterovesical junction (UVJ) - Allows retrograde flow of urine into ureters during bladder contraction - Risk: upper tract infections, renal scarring, hypertension, and chronic kidney disease

Clinical Presentation: - Often asymptomatic (discovered on prenatal ultrasound or during VCUG after UTI diagnosis) - Recurrent UTIs, fever, flank pain - Some present with prenatal hydronephrosis

Grading (International Reflux Grading System I-V): - Grade I: Contrast in ureter only - Grade II: Contrast in ureter, kidney collecting system; no blunting - Grade III: Mild dilation of collecting system and calyces with blunting of forniceal acuity - Grade IV: Moderate dilation; blunting of major calyces; absent papillary impressions - Grade V: Severe dilation; ureteral tortuosity; blunting; absent renal papillae

Management: - Grades I-II: Prophylactic antibiotics (nitrofurantoin, TMP-SMX); periodic reimaging - Grades III-V: Consider urology referral; endoscopic injection or open ureteral reimplantation - Continuous antibiotic prophylaxis reduces UTI incidence; controversial whether it reduces scarring

B. Posterior Urethral Valves (PUV)

Epidemiology: - Most common cause of lower urinary tract obstruction in males - Incidence: 1 in 4,000-25,000 male live births

Pathophysiology: - Obstructive leaflets in prostatic urethra (Williams classification: Types I-III) - Leads to bladder outlet obstruction, high intravesical pressure, VUR (80%), and renal damage

Clinical Presentation: - Prenatal: Bilateral hydroureteronephrosis, oligohydramnios, poor bladder emptying - Neonatal: Poor urinary stream, palpable abdominal mass (distended bladder), failure to void within 24 hours - Sepsis if complicated by infection - Chronic: Failure to thrive, developmental delay, CKD progression

Diagnosis: - Prenatal ultrasound: Bilateral upper tract dilation, thick-walled bladder, oligohydramnios - Postnatal VCUG: Dilated prostatic urethra, posterior urethral dilation, vesical thickening, VUR - Renal ultrasound: Assess degree of hydronephrosis and renal parenchymal thinning

Management: - Urgent: Catheter drainage to decompress system and allow recovery of renal function - Definitive: Endoscopic valve ablation (TURP equivalent in neonates) via cystoscopy - Long-term: Monitor renal function, address VUR if present, manage bladder dysfunction

C. Ureteropelvic Junction (UPJ) Obstruction

Epidemiology: - Most common intrauterine urinary tract anomaly - Incidence: 1 in 1,000-4,500 live births; higher on left side

Pathophysiology: - Functional or anatomic narrowing at UPJ transition - Leads to impaired urine drainage and progressive hydronephrosis

Clinical Presentation: - Majority asymptomatic, discovered on prenatal ultrasound (40-60% of cases) - Postnatal: Flank mass, hematuria, UTI, abdominal pain in older children - Rarely: severe renal insufficiency if bilateral

Diagnosis: - Prenatal ultrasound: Unilateral (typically) or bilateral hydronephrosis with normal bladder - Postnatal ultrasound: Graded hydronephrosis (mild, moderate, severe) - Diuretic renal scintigraphy: Gold standard; determines differential renal function and degree of obstruction - Differential function <15% may warrant nephrectomy; >20% suggests trial of conservative management

Management: - Conservative: Serial ultrasounds every 3-6 months; monthly urinalysis; prophylactic antibiotics controversial - Surgical: Pyeloplasty indicated if: worsening hydronephrosis, recurrent UTI, or symptoms - Outcome: Spontaneous resolution in 40-60% of cases; pyeloplasty success rate >95%

A. Definition and Epidemiology

KDIGO Definition (adapted for neonates): - Stage 1: Cr increase 1.5-1.9× baseline or UOP <0.5 mL/kg/hr for 6-12 hr - Stage 2: Cr increase 2-2.9× baseline or UOP <0.5 mL/kg/hr for ≥12 hr - Stage 3: Cr increase ≥3× baseline or UOP <0.3 mL/kg/hr for ≥24 hr, or anuria for ≥12 hr

Incidence: 10-24% of neonates in NICU; varies by gestational age and acuity of illness

B. Etiology by Category

Prerenal (most common, ~50%): - Hypotension, sepsis, dehydration, maternal medications (ACE inhibitors, NSAIDs) - Response to volume resuscitation

Intrinsic Renal (~25-40%): - Acute tubular necrosis (hypoxia-ischemia, nephrotoxins) - Pigment nephropathy (myoglobin, hemoglobin) - Acute glomerulonephritis (rare in neonates) - Hemolytic uremic syndrome - Thrombosis (renal artery or vein)

Postrenal (~10%): - Posterior urethral valves, severe VUR with obstruction, bilateral UPJ obstruction - Uric acid nephropathy, bilateral nephrolithiasis (rare)

C. Clinical Recognition

Key Findings: - Delayed passage of first urine (normal: within 24 hours of birth) - Serum creatinine elevation or failure to decline as expected - Oliguria (UOP <0.5 mL/kg/hr) despite adequate fluid intake - Anuria in severe cases - Hyperkalemia, hyperphosphatemia, hypocalcemia, metabolic acidosis - Pulmonary edema, hypertension, seizures (if severe)

Diagnostic Workup: - Renal ultrasound: Assess for hydronephrosis, echogenicity, size; rule out obstruction - Urinalysis: Proteinuria, hematuria suggest intrinsic renal disease - Urine electrolytes and osmolality (if sufficient urine): - FENa <1% suggests prerenal; >2% suggests ATN - FEU >35% suggests ATN (urea nitrogen spillage)

D. Management Principles

Acute Phase: 1. Establish IV access; assess volume status (birth weight vs. current, vital signs, capillary refill) 2. Place Foley catheter to accurately measure UOP 3. Send labs: BUN, creatinine, potassium, phosphate, calcium, magnesium, CBC, blood gas 4. Fluid management: - Calculate insensible losses (15-20 mL/kg/day in term; higher in preterm) - Add measured UOP + any other losses (ostomy, chest tube) - Hold beyond maintenance if oliguric; may require fluid restriction 5. Medication adjustments: Review all nephrotoxic drugs; adjust renally cleared medications 6. Hyperkalemia management (if K >6.5 mEq/L or EKG changes): - Calcium gluconate (inotropic effect, cardiac membrane stabilization) - Dextrose + insulin infusion or beta-agonists (shift K intracellularly) - Diuretics if fluid-responsive (furosemide) - Potassium binders (sodium polystyrene sulfonate in older neonates; limited data in very premature) - Consider CRRT (continuous renal replacement therapy) if refractory

Nutrition: - Avoid protein initially in acute AKI; resume when renal function stabilizing - High caloric density to minimize fluid volume

Renal Replacement Therapy (RRT): - Indicated if: potassium >7 mEq/L refractory to medical therapy, severe fluid overload, BUN >100 mg/dL, severe acidosis - CRRT preferred in hemodynamically unstable neonates over hemodialysis

Outcome: - Most neonatal AKI is reversible; recovery of renal function often within 1-2 weeks - Risk factors for persistent CKD: severe AKI, prematurity, low birth weight, sepsis

A. Minimal Change Disease (MCD)

Epidemiology: - Most common cause of nephrotic syndrome in children (85-90% of cases age 2-10 years) - Peak incidence: 2-6 years - Rare after age 10 years; if so, consider secondary causes

Pathophysiology: - T-cell dysfunction leads to loss of charge and size selectivity of glomerular filtration barrier - Podocyte foot process fusion seen on electron microscopy (reversible) - No glomerular deposits on immunofluorescence (“nil disease”)

Clinical Presentation: - Classic triad: Proteinuria (nephrotic range, >3.5 g/day), hypoalbuminemia (<2.5 g/dL), edema - Sudden onset of periorbital edema, pedal edema, ascites - Weight gain over 1-2 weeks (fluid retention) - Irritability, malaise, anorexia - Blood pressure typically normal (important differentiator from PSGN) - Normal renal function and normal complement levels (C3, C4)

Diagnostic Criteria: - Nephrotic-range proteinuria (UPr/Cr ratio >2-3 g/g in children) - Serum albumin <2.5 g/dL - Hyperlipidemia (cholesterol often >200 mg/dL) - Normal complement levels and normal ANA (excludes lupus, post-infectious GN)

Management: 1. Corticosteroid therapy (first-line): - Prednisone 2 mg/kg/day (max 80 mg/day) for 4-6 weeks, then alternate-day dosing × 4-6 weeks - Response rate: 85-90% of children achieve remission (urinary protein <4 mg/kg/day) - Remission typically occurs within 1-2 weeks of initiation 2. Diuretics: Furosemide for symptomatic edema; spironolactone if hypokalemia develops 3. ACE inhibitor or ARB: Start after initial remission to reduce proteinuria and slow progression 4. Prophylactic antibiotics: Penicillin V for asplenic risk (MCD increases susceptibility to encapsulated organisms) 5. Lipid management: Simvastatin if cholesterol persistently elevated 6. Fluid restriction: 1 mL/kg + measured losses during acute phase 7. Albumin infusion: Not routinely recommended; reserved for symptomatic severe hypoalbuminemia with respiratory compromise

Relapse: - 50% of children relapse; some become frequent relapsers (≥2 relapses in 6 months) - Relapse defined by return of nephrotic-range proteinuria - Frequently precipitated by viral infection, vaccine, or inadequate steroid taper - Repeat corticosteroid course for relapse; same response expected

Steroid-Resistant MCD: - 10-15% of patients fail to respond to 8-week course of adequate steroids - Consider secondary causes: focal segmental glomerulosclerosis (FSGS), lupus, drug-induced - Options: CNI (cyclosporine, tacrolimus), mycophenolate mofetil, rituximab - Renal biopsy recommended if steroid-resistant

A. Epidemiology and Pathophysiology

Incidence: 1-3% of children with streptococcal skin or throat infection

Pathophysiology: - Immune complex deposition (streptococcal antigen-antibody complexes) in glomeruli - Complement activation (C3 deposition); classic pathway involvement - Usually self-limited; complete renal recovery expected

B. Clinical Presentation

Classic Features: - History of group A streptococcal (GAS) throat infection (pharyngitis) 1-3 weeks prior - OR skin infection (pyoderma, impetigo) 3-6 weeks prior - Sudden onset of hematuria (smoky/cola-colored urine) - Periorbital edema, hypertension (15-30% have BP >95th percentile for age/height) - May have oliguria, but nephrotic-range proteinuria uncommon - Often mild systemic symptoms (malaise, low-grade fever)

Laboratory Findings: - Hematuria (RBCs and RBC casts) on urinalysis - Mild-to-moderate proteinuria (<3.5 g/day; nephrotic-range is rare) - Elevated ESR and normal CRP (reversed from typical infection) - Reduced C3 complement (low early, normalizes by 6-8 weeks) - Normal C4 complement (helps distinguish from lupus) - Elevated streptococcal titers: ASO (antistreptolysin O), anti-DNase B - Mild renal insufficiency (Cr elevation <2×) in 50% of children

Renal Biopsy Findings (if performed): - Acute proliferative GN - Subepithelial “hump” deposits on electron microscopy (pathognomonic for PSGN) - C3-dominant immunofluorescence

C. Differential Diagnosis

D. Management

Conservative Approach (Standard): - Supportive care: fluids, salt restriction, diuretics if hypertensive or edematous - Antibiotics: Treat active strep infection; eradicate carrier state - Monitor: Weekly urinalysis, BP checks, renal function during acute phase - Most children achieve normal urinalysis within 4-6 weeks - 95% have complete resolution of hematuria by 1 year

Immunosuppression: - NOT recommended for routine PSGN (unlike lupus or IgA nephropathy) - Reserved for rapidly progressive GN with crescent formation or severe renal dysfunction

Complications (rare): - Acute hypertensive encephalopathy: Treat with labetalol, hydralazine, nicardipine; diuretics and fluid restriction - Pulmonary edema: Furosemide, oxygen, consider dialysis if unresponsive - RPGN (crescent formation): May require plasmapheresis, immunosuppression

A. Alport Syndrome

Genetics: - Type IV collagen (COL4A) gene mutation - X-linked dominant (85%, males more severely affected) - Autosomal recessive (15%, affects both sexes equally) - Autosomal dominant (rare, <1%)

Pathophysiology: - Defect in type IV collagen (GBM, cochlea, eye) - Progressive GBM thinning followed by fragmentation (“basket-weave” on EM) - Loss of α3, α4, α5 chains of type IV collagen

Clinical Presentation: - Males (X-linked): Persistent microscopic hematuria from infancy; progressive proteinuria by 20s; ESRD by 30s - Females (X-linked): Milder phenotype; often asymptomatic hematuria; ESRD rarely before 50s - Extrarenal manifestations: - Sensorineural hearing loss (high-frequency, progressive, bilateral) - Ocular: Anterior lenticonus (pathognomonic but rare), retinal flecks (“basket-weave”), temporal thinning - Other: Macrothrombocytopenia (large platelets, mild thrombocytopenia), skin abnormalities

Diagnosis: - Renal biopsy with electron microscopy: GBM splitting and lamination (classic finding) - Genetic testing: COL4A gene sequencing - Skin or kidney biopsy immunostaining for α3 or α5 chains of type IV collagen

Management: - ACE inhibitors/ARBs: Slow progression of proteinuria and renal dysfunction - Hearing aids and audiology follow-up - Ophthalmology evaluation for ocular complications - Renal replacement therapy when ESRD reached

B. Thin Basement Membrane Disease (TBMD)

Genetics: - Autosomal dominant or recessive (COL4A mutations, same genes as Alport) - May represent benign familial hematuria or forme fruste Alport

Pathophysiology: - Isolated GBM thinning (<250 nm, normal >300 nm) on electron microscopy - No progressive damage; no extrarenal manifestations

Clinical Presentation: - Asymptomatic microscopic or episodic gross hematuria - Often discovered incidentally during workup for hematuria - Normal renal function - Normal hearing and vision - Normal platelet count and morphology

Diagnosis: - Renal biopsy electron microscopy: Thin GBM without splitting/lamination or immune deposits - Immunofluorescence: Negative (no deposits)

Prognosis: - Excellent; no progressive renal disease - Hematuria may persist indefinitely but does not cause renal insufficiency - Counseling: Reassurance, avoid nephrotoxic drugs and contact sports if hematuria visible

A. Epidemiology and Risk Factors

Incidence: - 7-8% of girls; 2% of boys by age 5 years - Higher in uncircumcised males <1 year (3-5×) - Risk of renal scarring: 15-20% if untreated; reduced with early antibiotic therapy

Risk Factors for Serious Renal Infection: - Age <2 years - Male sex - Fever >39°C - Duration of fever >2 days - Underlying urologic abnormality (CAKUT, VUR)

B. Diagnostic Approach by Age

Infants <2 Years (Highest Risk): - Cannot localize symptoms; cannot report dysuria - Approach: Assume pyelonephritis until proven otherwise - Urine collection: Straight catheter or suprapubic aspiration (most reliable); avoid bagged specimens (high contamination) - Imaging: Renal ultrasound or dimercaptosuccinic acid (DMSA) scan to assess renal scarring - Empiric broad-spectrum antibiotics pending culture

Children 2-5 Years: - Symptoms may be nonspecific (fever, malaise, abdominal pain) - May or may not have dysuria symptoms - Approach: Risk stratification; consider imaging if atypical features - Urine: Clean-catch or catheterized specimen preferred - Cystourethrogram (VCUG) if first febrile UTI or recurrent UTI

Children >5 Years: - Classic dysuria, frequency, urgency - Lower risk of upper tract involvement and scarring - Approach: Treat as cystitis if symptoms typical and no fever - Imaging: VCUG/ultrasound if recurrent or if pyelonephritis documented

C. Diagnostic Criteria

Urinalysis: - Pyuria (WBC >5-10/hpf, nitrites, leukocyte esterase) - Bacteriuria: Any bacteria in catheterized specimen; >10⁵ CFU/mL in clean-catch

Urine Culture (gold standard): - Gram-negative organisms: E. coli (80%), Klebsiella, Proteus, Enterococcus - Gram-positive: Staphylococcus saprophyticus, Enterococcus faecalis - Contaminants: Multiple organism types, mixed flora - Significant growth: ≥10⁵ CFU/mL (clean-catch), ≥10² CFU/mL (catheterized), any growth (suprapubic aspiration)

D. Imaging Recommendations

After First Febrile UTI: - Renal ultrasound: Assess for hydronephrosis, pyelonephritis, scarring - VCUG (voiding cystourethrogram): Detect VUR - Timing of VCUG: Often deferred 4-6 weeks after acute infection to allow inflammation to resolve

Risk Stratification: - High risk (Image promptly): Age <2 years, males, atypical/severe pyelonephritis - Moderate risk: Age 2-5 years, typical febrile UTI - Low risk (Selective imaging): Age >5 years, typical symptoms, good response to antibiotics

A. Pathophysiology of Growth Failure in CKD

Mechanisms: 1. Metabolic acidosis: Increased protein catabolism; decreased anabolic drive 2. Protein-energy wasting: Anorexia, uremia, inadequate dialysis 3. Renal osteodystrophy: Secondary hyperparathyroidism, FGF23 elevation 4. Uremia: Inhibitory effect on growth hormone and IGF-1 5. Anemia: Reduced oxygen delivery; decreased erythropoietin 6. Hypertension: Renin-angiotensin activation; may affect growth 7. Medication effects: Corticosteroids (if given for underlying disease) 8. Nutritional deficiencies: Inadequate dietary intake; losses in dialysate

Incidence: - 30-40% of children with CKD stages 3-5 have height <5th percentile for age - Growth velocity declines as GFR falls below 30 mL/min/1.73 m²

B. Clinical Assessment

Growth Measurement: - Height and height velocity every 3-6 months - Plot on standardized growth curves (CDC, WHO) - Height velocity <3 cm/year in a child suggests pathologic growth failure - Mid-parental height calculation: account for genetic potential

Associated Features: - Skeletal radiographs: Metaphyseal changes, decreased bone density - Laboratory: PTH, FGF23, phosphate, calcium, alkaline phosphatase, albumin, prealbumin - Growth hormone stimulation test (if severe growth failure refractory to management)

C. Management

Nutritional Interventions: 1. Adequate protein intake: 100% of recommended daily allowance (RDA) or higher (RDA for age, but some recommend higher) 2. Caloric supplementation: May require 110-130% of RDA for age 3. Phosphate restriction: Limit to <1,000 mg/day; adjust as renal function declines 4. Sodium and fluid restriction: As needed for hypertension, edema 5. Enteral feeding: Nasogastric or gastrostomy for children unable to meet needs orally 6. Nutritionist consultation: Critical; involves dietitian specialized in pediatric renal disease

Medical Management: 1. Correction of metabolic acidosis: Sodium bicarbonate or sodium citrate to target HCO₃⁻ 22-24 mEq/L 2. Management of secondary hyperparathyroidism: - Phosphate binders (calcium carbonate, sevelamer, lanthanum) - Calcitriol (activated vitamin D): Increases intestinal calcium absorption - Calcimimetics (cinacalcet): Reduces PTH secretion 3. Anemia management: Erythropoietin-stimulating agents (ESAs) + iron supplementation to target Hgb 10-11 g/dL 4. Blood pressure control: Antihypertensives; ACE inhibitors or ARBs for additional renoprotection 5. Growth hormone therapy: - Recombinant human growth hormone (rhGH): Dose 0.35 mg/kg/week (divided into 6-7 daily injections) - Indication: Growth failure despite optimized nutrition, metabolic management, and PD/dialysis - Efficacy: Improves growth velocity by 3-6 cm/year in responders - Duration: Typically given until final height achieved or renal transplantation - Monitoring: Insulin-like growth factor-1 (IGF-1) levels; screen for glucose intolerance - Cost and logistics: Significant expense; requires patient/family commitment to daily injections

Dialysis Optimization: - Adequate dialysis dose (Kt/V ≥1.2 for hemodialysis; CKD-stage adjusted clearance for PD) - Reduced protein catabolic rates with adequate dialysis

Renal Transplantation: - Often results in catch-up growth, especially if transplanted before puberty - Benefits of shorter time on dialysis

Related Student Handouts

• Student Handout: Congenital Renal Anomalies
• Student Handout: Tubular Disorders
• Student Handout: CKD Complications

Clinical References (01-Clinical-Medicine/Nephrology)

• Nephrology Hub - Core clinical content
• CKD Hub - Chronic kidney disease management
• AKI Hub - Acute kidney injury diagnosis and management
• Genetic & Hereditary Kidney Diseases

Last Updated: 2026-02-12